Preparation of 2-mercaptoimidazoles



Patented Feb. 12, 1952 2,585,388 PREPARATION OF'Z-MERCAPTGIMIDAZOLES Reuben G. Jones, Indianapolis, Ind., assignor to Eli Lilly and Compan corporation of Indiana y, Indianapolis, Ind, a

No Drawing. Application November 17-, 1948; Serial No. 60,631

invention relates to. organic chemical procasses, and more particularly to a process. of; preparing 2 =mercaptoimidazoles.

It, is an object of myv invention to provide a Simple. method of preparing imidazoles which have at least a mercapto substituent in the Zeppsition, such as Z-mercaptoimidazole and substitution products of Z-mercaptoimidazole in which substituents may be present in either or both of the 1. and 4 po itions of he. im d le nucl Other objects will be apparent from the following disclosure.

In pursuance of the above and other objects, I'have provided a process for preparing 2emercaptoimidazoles by heat-decarboxylation of ,2,-

in which R and R1 represent substituents attached respectively to the 1 and 4 positions of the imidazole nucleus.

Broadly stated, my process comprises heatinga 2-mercapto-5'-carboxyimidazole to a temperature above the melting point of the imidazolecarboxylioacid; whereupon decarboxylation occurs, as is evidenced by the liberation of carbon dioxide from the molten imidazole compound. Surprisingly, the mercapto compound group which is attached to the 2-position of the imidazole group is unaffected by the relatively high temperature required' forthe decarboxylation, e. g. from about A preferred manner of carrying out my process is as follows: The 2-mercapto-5-carboxyimidazole which is to be decarboxylated' is placed in a suitable container, and while nitrogen is passed into the container, heat is applied to the container and its contents until the imidazole compound melts and a brisk evolution of carbon dioxide oc- 4 Claims. (Cl. 260-.-309-).

curs. Heating is continued until the evolution of" carbon dioxide ceases. The contents of the container are then cooled and are purified by recrystallization.

It is desirable that duringthe'heating process the material subjected tov decarboxylation be protected-from atmospheric oxygen in order to avoid extensive decomposition of the decarboxylated imidazole. To avoid exposure to oxygen, the reaction preferably is carried out under an inert gas, for example, nitrogen or carbon dioxide. However, sufficient protection is generally afforded if a container havinga relatively small neck orifice is employed. In this case, the carbon dioxide liberated during the reaction serves to insulate the reaction, mixture from atmospheric oxygen.

The imidazole which is obtained by decarboxylation may be purified in any convenient manner, for example, by crystallization from a suitable solvent.

My invention is furtheriillustrated bythe following examples.

Example 1.-Preparation of 1-phenyZ-2-mercaptoimidazole the following formula .HQQOH.

1 -ph enyl-2 mercaptoimidazgle represented by acetone, The resulting solution is treated with a small amount of .decolorizing carbon and iiitered. The filtrate is evaporated by heat until solid 1ephenyle2-mercaptoimidazole appears in the solidi 10.11, and. ml. of loweboiling petrole un ether are addedand the. mixture is. cooled and allowed to stand. until crystallization is complete. The crystalline 1-phenyl-2-mercaptoimidazole is filtered off and dried. r

8.5 g. of 1-phenyl-2-mercaptoimidazole melting atabout -18190. are obtained. This represents a yield of about 97 percent ofytheamount theoretically possible.

The 1-phenyl-2-mercapto 5 imidazolecarboxylic acid used in this example can be prepared as follows: 62 g. of N formyl-N-phenylglycine ethyl ester and 61 g. of ethyl formate are mixed and the mixture is cooled in an ice bath. To

' filtered.

the cooled mixture are added with stirring over a period of about one hour, 22 g. of sodium methoxide suspended in about '70 ml. of dry benzene. The mixture is then allowed to stand in the refrigerator for several hours. The mixture is extracted with 150 ml. of water whereby an aqueous solution of the sodium enolate salt of N-formyl- N-phenyl-C-formylglycine ethyl ester is obtained. To the aqueous extract are added 62 ml. of 12 N hydrochloric acid and the solution is treated with 40 g. of sodium thiocyanate. During the addition of the hydrochloric acid and sodium thiocyanate the reaction mixture is kept cool. The reaction mixture is then heated to about 90 C for 1 hour, whereupon l-phenyl-Z-mercapto- S-carbethoxyimidazole, which is formed in the reaction, crystallizes. The mixture is cooled and 62 g. of 1-phenyl-2-mercapto-5-carbethoxyimidazole are obtained.

30 g. of 1-phenvl-2-mercapto-5-carbethoxyimidazole are suspended in 150 ml. of 1.7 N sodium hydroxide solution and the mixture is warmed to about 80 C. for 2 hours, whereupon the ester is hydrolyzed. The solution is acidified with hydrochloric acid and the 1-phenyl-2-mercapto-5- imidazolecarboxylic acid precipitates. The acid is washed with a small amount of cold water and dried. 26 g. of 1-phenyl-2-mercapto-5-imidazolecarboxylic acid are obtained.

Example 2 1-cyclohexyl-2-mercaptoimidazole represented by the following formula is prepared as follows: 11.4 g. (0.05 mol) of. .1- cyclohexyl-2-mercapto 5 imidazolecarboxylic acid are decarboxylated according to the procedure described in Example 1, by heating the 1-cyclohexyl-2-mercapto-5 imidazolecarboxylic acid to about 240 C.

8.1 g. of 1-cyclohexyl-2-mercaptoimidazole are obtained. It melts at about 173-174 C. after recrystallization from acetone-petroleum ether mixture. Example 3.--Preparation of Z-mercaptoz'midazole 2-mercaptoimidazole represented by the following formula HC==CE l ya.

Example 4.-Prepamtion of I-methyl-Z- mercaptozmidazole 1-methyl-2-mercaptoimidazole represented by the formula is prepared from 1 methyl 5 carboxy-2-mercaptoimidazole by the procedure described in Example 1. 1-methyl-2-mercaptoimidazole melts at about 148-150 C.

. The 1-methyl-2-mercapto-5-carboxylio acid is obtained by alkaline hydrolysis of its methyl ester which can be prepared from N-formyl-N-methylglycine .methyl ester according to the procedure described in Example 1.

Example 5 Melting Compound point 0 O l-ethyl-Z-mercaptoimidazole 68-70 l-propyl-Z-mercaptoimidazole 1. -116 i-n-butyl-2-mercaptoimidazole 80-81 l-isobutyl-Z-mercaptoimidazole 137-138 l-tertiery-butyl-Z-mercaptoimidazole 189-190 l-secondary-heptyl-2-mcrcaptoimidazole 72-73 1-allyl-2-mercaptoimldazcle 73-74 l-benzyl-2-mercaptolmidazole -140 l-phenethyl-Z-moi-captoimidazole l66-167 l-ethyH-methyl-2-mereaptoimidazolc 208-210 4-ethyl-2-mcrcaptoimidazole -167 i-propyl-2-mercaptoimidazole 183-184 4-hexyl-2mercaptoimidazole 115-116 4-cyclopentyl-Z-mercaptoimidazole 218-221 4-benzyl-2-mercaptoimidazole l 223-224 i 'I claim:

1. The method of preparing Z-mercaptoimidazoles whichcomprises heating a 2-mercapto-5- carboxyimidazole between the temperature of its melting point and a temperature of about 270 C. to produce decarboxylation of the 2-mercapto-5- carboxyimidazole, and recovering the imidazole compound which is produced.

2. The method of preparing 2-mercaptoimidazoleswhich comprises heating a 2-mercapto-5- carboxyimidazole to a temperature between about 230 C. and 270 C. until evolution of carbon dioxide has substantially ceased, and recovering the imidazole compound which is produced. I

3. The method of preparing 1-methyl-2-mer captoimidazole which comprises heating 1- methyl-2-mercapto-5-carboxyimidazole to a temperature between 230 C. and 270 C. until evolution of carbon dioxide has substantially ceased, and recovering the 1 methyl 2 mercaptoimidazole which is produced.

4. The method of preparing 1-phenyl-2-mercaptoimidazole which comprises heating 1- phenyl-2-mercapto-5-carboxyimidazole to a temperature between 230 C. and 270 C. until evolution of carbon dioxide has substantially ceased; and recoverin the 1 phenyl 2 mercaptoimidazole which is produced.

REUBEN G; JONES.

REFERENCES CITED v Beilstein, 4th ed. (1936) vol. 25, p. 216. 

1. THE METHOD OF PREPARING 2-MERCAPTOIMIDAZOLES WHICH COMPRISES HEATING A 2-MERCAPTO-5 CARBOXYLIMIDAZOLE BETWEEN THE TEMPERATURE OF ITS MELTING POINT AND A TEMPERATURE OF ABOUT 270* C. TO PRODUCE DECARBOXYLATION OF THE 2-MERCAPTO-5 CARBOXYLIMIDAZOLE, AND RECOVERING THE IMIDAZOLE COMPOUND WHICH IS PRODUCED. 